A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity Versus Functional Activities.

A Bivalent Ligand Targeting the Putative Mu Opioid Receptor and Chemokine Receptor CCR5 Heterodimers: Binding Affinity versus Functional Activities.

Medchemcomm. 2013 May 1; 4(5): 847-851
Yuan Y, Arnatt CK, El-Hage N, Dever SM, Jacob JC, Selley DE, Hauser KF, Zhang Y

Opioid substitution and antiretroviral therapies have steadily increased the life spans of AIDS patients with opioid addiction, while the adverse drug-drug interactions and persistence of HIV-associated neurocognitive disorders still require new strategies to target opioid abuse and HIV-1 comorbidities. A bivalent ligand 1 with a 21-atom spacer was thus synthesized and explicitly characterized as a novel pharmacological probe to study the underlying mechanism of opioid-enhanced NeuroAIDS. The steric hindrance generated from the spacer affected the binding affinity and Ca(2+) flux inhibition function activity of bivalent ligand 1 at the chemokine receptor CCR5 more profoundly than it did at the mu opioid receptor (MOR). However, the CCR5 radioligand binding affinity and the Ca(2+) flux inhibition function of the ligand seemed not necessarily to correlate with its antiviral activity given that it was at least two times more potent than maraviroc alone in reducing Tat expression upon HIV-1 infection in human astrocytes. Furthermore, the ligand was also about two times more potent than the simple mixture of maraviroc and naltrexone in the same viral entry inhibition assay. Therefore bivalent ligand 1 seemed to function more effectively by targeting specifically the putative MOR-CCR5 heterodimer in the viral invasion process. The results reported here suggest that a properly designed bivalent ligand may serve as a useful chemical probe to study the potential MOR-CCR5 interaction during the progression of NeuroAIDS. HubMed – addiction

Mental health care Monitor Older adults (MEMO): monitoring patient characteristics and outcome in Dutch mental health services for older adults.

Int J Methods Psychiatr Res. 2013 May 16;
Veerbeek M, Oude Voshaar R, Depla M, Pot AM

Information on which older adults attend mental health care and whether they profit from the care they receive is important for policy-makers. To assess this information in daily practice, the “Mental health care Monitor Older adults” (MEMO) was developed in the Netherlands. The aim of this paper is to describe MEMO and the older adults who attend outpatient mental health care regarding their predisposing and enabling characteristics and need for care. In MEMO all patients referred to the division of old age psychiatry of the participating mental health care organisations are assessed at baseline and monitored at 4, 8 and 12-month follow-up. Primary outcomes are mental and social functioning, consumer satisfaction, and type of treatment provided (MEMO Basic). Over the years, MEMO Basic is repeated. In each cycle, additional information on specific patient groups is added (e.g. mood disorders). Data collection is supported by a web-based system for clinicians, including direct feedback to monitor patients throughout treatment. First results at baseline showed that the majority of patients that entered the division of old age psychiatry was female (69%), had low education (83%), lived alone (53%), was depressed (42%) and had a comorbid condition (82%). It seemed that older immigrants were not sufficiently reached. The current study is the first in the Netherlands to evaluate patient characteristics and outcome in mental health care provided for older adults in day-to-day practice. If MEMO works out successfully, the method should be extended to other target groups. Copyright © 2013 John Wiley & Sons, Ltd. HubMed – addiction

Cocaine self-administration behavior in inbred mouse lines segregating different capacities for inhibitory control.

Psychopharmacology (Berl). 2013 May 17;
Cervantes MC, Laughlin RE, Jentsch JD

RATIONALE: Various dimensions of impulsivity have been linked to substance abuse and dependence, both as consequences of, and as predisposing factors to addiction. With respect to the latter, they may be quantitative indicators of liability for substance use disorders (SUD) and aid in determining underlying genetic influences. We have previously determined that inhibitory control over impulsive responding, as measured by a reversal learning task, is heritable and under substantial genetic control, however their role as explaining variables for aspects of SUD have not been well explored. OBJECTIVE: The aim of this study was to test for an association between genetically determined differences in inhibitory control and addiction-related phenotypes, such that phenotypes of poor inhibitory control would predict propensity for elevated operant drug-seeking and -taking behaviors. METHODS: Mice from BxD strains with either good reversal learning (GRL) or poor reversal learning (PRL) ability were tested for intravenous cocaine self-administration under FR1, FR2, and FR5 reinforcement schedules. Additionally, locomotor responses to experimenter-delivered cocaine were assessed. RESULTS: Compared to GRL strains, PRL strains acquired self-administration behavior more rapidly and administered cocaine at greater rates under all schedules of reinforcement, without any differences in discrimination index. In addition, PRL mice also exhibited increased responding during time-out periods. PRL strains also showed larger locomotor responses to 10 or 20 mg/kg injections of cocaine. CONCLUSIONS: These studies demonstrate that heritable strain differences in inhibitory control do influence drug self-administration, thus suggest that genetically driven impulsivity of this type may predispose susceptibility to drug abuse and addiction. HubMed – addiction

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